Patent EA-001403-B1 (EA)
Title: Substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist activity to ppar-gamma
Inventor: WILLSON TIMOTHY MARKMOOK ROBER
IPC: A61P3/00
Filed: 1997-02-26
Abstract: 1. A compound having the formula (I)   wherein A is selected from the group consisting of: (i) phenyl, wherein said phenyl is optionally substituted by one or more halogen atoms, C1-6alkyl, C1-3alkoxy, C1-3fluoroalkoxy, nitrile, or -NR<7>R<8>, where R<7> an d R<8> are independently hydrogen or C1-3alkyl; (ii) a 5- or 6- membered heterocyclic group containing at least one heteroatom  selected from oxygen, nitrogen and sulfur; and optionally substituted by one or more halogen atoms, C1-3alkyl, C1-3alkoxy group, C0-3alkylene-NR<9>R<10> (where each R<9> and R<10> is independently hydrogen, C1-3alkyl, -SO2C1-3alkyl, or -CO2C1-3alkyl, -SO2NHC1-3alkyl, C0-3alkyleneCO2H, C0-3alkyleneCO2C1-3alkyl, -OCH2C(O)NH2, -C1-3fluoroalkyl, -CN or -SC1-6alkyl; and (iii) a fused bicyclic ring  wherein ring C represents a heterocyclic group as defined in point (ii) above, which bicyclic ring is attached to group B via a ring atom of ring C; B is selected from the group consisting of: (iv) C1-6alkylene; (v) -MC1-6alkylene or C1-6alkyleneMC1-6alkylene, wherein M is O, S, or -NR<2> wherein R<2> represents hydrogen or C1-3alkyl; (vi) a 5- or 6- membered heterocyclic group containing at least one nitrogen heteroatom and optionally at least one further heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by C1-3alkyl; and (vii) Het-C1-6alkylene, wherein Het represents a heterocyclic group as defined in point (vi) above; Alk represents C1-3alkylene; R<1> represents hydrogen or C1-3alkyl; Z is selected from the group consisting of: (viii) -(C1-3alkylene)phenyl, which phenyl is optionally substituted by one or more halogen atoms; and (ix) -NR<3>R<4>, wherein R<3> represents hydrogen or C1-3alkyl, and R<4> represents -Y-(C=O)-T-R<5>, or-Y-(CH(OH))-T-R<5>, wherein: (a) Y represents a bond, C1-6alkylene, C2-6alkenylene, C4-6cycloalkylene or cycloalkenylene, a heterocyclic group as defined in point (vi) above, or phenyl optionally substituted by one or more C1-3alkyl groups and/or one or more halogen atoms; (b) T represents a bond, C1-3alkyleneoxy group, -O- or -N(R<6>)-, wherein R<6> represents hydrogen or C1-3alkyl; (c) R<5> represents C1-6alkyl, C4-6cycloalkyl or cycloalkenyl, phenyl (optionally substituted by one or more: halogen atoms, C1-3alkyl, C1-3alkoxy group, C0-3alkylene-NR<9>R<10> where each R<9> and R<10> is independently hydrogen, C1-3alkyl, -SO2-C1-3alkyl, or -CO2C1-3alkyl, -SO2NHC1-3alkyl, C0-3alkyleneCO2H, C0-3alkyleneCO2C1-3alkyl or -OCH2C(O)NH2), a 5- or 6-membered heterocyclic group as defined in point (ii) above, a bicylic fused ring   wherein ring D represents a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by (=O), which bicyclic ring is attached to T via a ring atom of ring D, or -C1-6alkyleneMR<11>, M is O, S, or -NR<2> wherein R<2> and R<11> are independently hydrogen or C1-3alkyl; or a tautomeric form thereof, and/or a pharmaceutically acceptable salt or solvate thereof. 2. The compound of claim 1 wherein each of said 5- or 6- membered heterocyclic groups is independently selected from the group consisting of substituted or unsubstituted imidazolidinyl, piperidyl, piperazinyl pyrrolidinyl, morpholinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, or tetrazolyl, each of them is optionally substituted by substituents, mentioned in claim 1. 3. A compound according to claim 1 or 2, wherein A represents phenyl, pyridyl, piperazinyl or benzoxazolyl, any of which is optionally substituted by one or more C1-3alkyl. 4. A compound according to claim 3, wherein A represents phenyl, piperazinyl or pyridyl. 5. A compound according to any of claims 1-4, wherein B represents C1-3alkylene, -N(CH3)C1-3alkylene or HetC1-6alkylene wherein Het represents a 5-membered heterocyclic group containing at least one nitrogen atom and optionally at least one further heteroatom selected from oxygen and sulphur, substituted or unsubstituted by C1-3alkyl. 6. A compound according to claim 5 wherein B represents -N(CH3)(CH2)2, oxazolyl-C1-6alkylene wherein said oxazolyl is optionally substituted by C1-3 alkyl, or thiazolyl which is optionally substituted by C1-3alkyl. 7. A compound according to any of claims 1-6, wherein Alk represents methylene. 8. A compound according to any of claims 1-7, wherein R<1> represents hydrogen, methyl or ethyl. 9. A compound according to claim 8, wherein R<1> is hydrogen. 10. A compound according to any of claims 1-9, wherein Z represents -NR<3>R<4> wherein R<3> and R<4> are as defined in claim 1. 11. A compound according to claim 10 wherein R<3> is hydrogen. 12. A compound according to claim 10 or 11, wherein R<4> represents -Y(C=O)-T-R<5> wherein R<5> is as defined in claim 1. 13. The compound of claim 8 wherein Y is phenyl optionally substituted by one or more C1-3alkyl groups and/or one or more halogen atoms. 14. The compound of claim 9 wherein T is a bond or -O-. 15. A compound according to claim 12, 13 or 14 wherein R<5> represents C1-3 alkyl or phenyl (optionally substituted by one or more halogen atoms or one or more C1-3alkyl groups). 16. The compound of claim 10 wherein said NH and said (C=O) are positioned ortho to each other on Y (which is phenyl), T is a bond or -O-, R<5> is C1-6alkyl, or phenyl (optionally substituted by one or more: halogen atoms, C1-3alkyl, C1-3 alkoxy groups, C0-3alkylene-NR<9>R<10> where each R<9> and R<10> is independently hydrogen, C1-3alkyl, -SO2C1-3alkyl, or -CO2C1-3alkyl, -SO2NHC1-3alkyl, C0-3alkyleneCO2H, C0-3alkyleneCO2C1-3alkyl or -OCH2C(O)NH2). 17. A compound according to claim 15 or 16 wherein R<4> represents   wherein R<13> is phenyl or OCH3. 18. A compound according to claim 1 of formula (Ia)   wherein A and B are as described in claim 1 and Ar represents a phenyl or a 5 or 6 membered heteoaryl group containing at least the heteroatom selected from oxygen, nitrogen and sulphur and optionally substituted by one or more: halogen atoms, C1-3alkyl, C1-3 alkoxy groups, C0-3alkylene-NR<9>R<10> (where each R<9> and R<10> is independently hydrogen, C1-3alkyl, -SO2C1-3alkyl, or -CO2C1-3alkyl, -SO2NHC1-3alkyl), C0-3alkyleneCO2H, C0-3alkyleneCO2C1-3alkyl or -OCH2C(O)NH2, -C1-3fluoroalkyl, -CN or -SC1-6alkyl and solvates thereof. 19. A compound according to claim 1 having the formula (I)   wherein A is selected from the group consisting of:  (i) phenyl optionally substituted by one or more halogen atoms; (ii) a 5- or 6- membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur; andand optionally substituted by one or more: halogen atoms, C1-3alkyl, C1-3 alkoxy groups, C0-3alkylene-NR<9>R<10> (where each R<9> and R<10> is independently hydrogen, C1-3alkyl, -SO2C1-3alkyl, or -CO2C1-3alkyl, -SO2NHC1-3alkyl), C0-3alkyleneCO2H, C0-3alkyleneCO2C1-3alkyl, -OCH2C(O)NH2, -C1-3fluoroalkyl, -CN or -SC1-6alkyl; and (iii) a fused bicyclic ring   wherein ring C represents a heterocyclic group as defined in (ii) above, which bicyclic ring is attached to group B via a ring atom of ring C; B is selected from the group consisting of: (iv) C1-6alkylene; (v) -NR<2>C1-6alkylene, wherein R<2> represents hydrogen or C1-3alkyl; (vi) a 5- or 6- membered heterocyclic group containing at least one nitrogen  heteroatom and optionally at least one further heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by C1-3alkyl; and (vii) Het-C1-6alkylene, wherein Het represents a heterocyclic group as defined in point (vi) above; Alk represents C1-3alkylene; R<1> represents hydrogen or C1-3alkyl; Z is selected from the group consisting of: (viii) -(C1-3alkylene)phenyl, which phenyl is optionally substituted by one or more halogen atoms; and (ix) -NR<3>R<4>, wherein R<3> represents hydrogen or C1-3alkyl, and R<4> represents -Y-(C=O)-T-R<5>, or -Y-(CH(OH))-T-R<5>, wherein: (a) Y represents a bond, C1-6alkylene, C2-6alkenylene, C4-6cycloalkylene or cycloalkenylene, a heterocyclic group as defined in point (vi) above, or phenyl optionally substituted by one or more C1-3alkyl groups and/or one or more halogen atoms; (b) T represents a bond, C1-3alkyleneoxy group, -O- or -N(R<6>)-, wherein R<6> represents hydrogen or C1-3alkyl; (c) R<5> represents C1-6alkyl, C4-6 cycloalkyl or cycloalkenyl, phenyl optionally substituted by one or more halogen atoms or one or more C1-3alkyl groups, a 5- or 6- membered heterocyclic group as defined in point (ii) above, or a bicylic fused ring   wherein ring D represents a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by (=O), which bicyclic ring is attached to T via a ring atom of ring D, or a tautomeric form thereof, and/or a pharmaceutically acceptable salt or solvate thereof. 20. A compound as claimed in claim 1 which is selected from the group consisting of: 3-(4-benzyloxy-phenyl)-2(S)-(1-methyl-3-oxo-3-phenyl-propenylamino)-propionic acid dicyclohexylamine salt; 3-(4-benzyloxy-phenyl)-2(S)-(1-methyl-3-oxo-3-phenyl-propenylamino)-propionic acid methyl ester; 2(S)-(2-benzoyl-cyclohex-1-enylamino)-3-(4-benzyloxy-phenyl)-propionic acid dicyclohexylamine salt; 2-(2-benzoylphenylamino)-3-(4-benzyloxyphenyl) propanoic acid; 3-(4-benzyloxy-phenyl)-2-(2-benzyloxy-phenylamino)-propionic acid methyl ester; 3-(4-benzyloxy-phenyl)-2-(phenylcarbamoyl-phenylamino)-propionic acid methyl ester; 3-(4-benzyloxy-phenyl)-2-[2-(piperidine-1-carbonyl)-phenylamino]-propionic acid methyl ester; 2-(3-benzoyl-thiophen-2-yl-amino)-3-(4-benzyloxy-phenyl)-propionic acid; 2-(2-benzoyl-thiophen-3-yl-amino)-3-(4-benzyloxy-phenyl)-propionic acid; 3-(4-benzyloxy-phenyl)-2(S)-[(4-oxo-4H-chromene-3-carbonyl)-amino]-propionic acid methyl ester; 2-(2-benzoyl-phenylamino)-3-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-phe